Gene therapy in patients with transfusion-dependent b-thalassemia (N Engl J Med. 2018;378:1479-93)

Gene therapy for thalassemia is keenly awaited. Results of a multinational (USA, Australia, France, Thailand and Germany) collaboration were reported this year. Mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent b-thalassemia were obtained. The cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution. The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning.

At a median of 26 months (range 15-42 mo) after infusion of the gene-modified cells, all but one of the 13 patients who had a non-b0/b0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g/dL, and the levels of total hemoglobin ranged from 8.2 to 13.7 g/dL. The researchers concluded that gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe b-thalassemia without serious adverse events related to the drug product.

Patients with B-cell ALL, T-cell ALL or T-NHL were administered 3 and 5 g/m2 of MTX (24　h infusion), respectively. Six doses of leucovorin (15　mg/m2/dose), instead of recommended three (for optimally reduced levels) at standard timing (42　h from start of HD-MTX) were administered. Hydration was continued for 72　h, instead of the recommended 30　h. Serum creatinine and urine pH were measured at baseline, 24 h and 48　h. The volume of hydration was increased for a serum creatinine　>1.25 times the baseline. The study included 100 cycles of HD-MTX in 53 patients: B-ALL 25 patients (51 cycles), T-ALL 16 patients (28 cycles), T-NHL 10 patients (18 cycles), and relapsed ALL 2 patients (3 cycles). Toxicities included mucositis (32%), diarrhea (10%) and febrile neutropenia (9%). The authors concluded that it is safe to administer 3 or 5 g/m2 of MTX (24　hr infusion) without measuring MTX levels, with extended hydration, additional doses of leucovorin, and monitoring of serum creatinine and urine pH.

Researchers randomly assigned 152 participants ³12 years of age, who had been receiving episodic treatment with factor VIII, to receive a subcutaneous maintenance dose of 1.5 mg/kg/week of emicizumab (group A) or 3 mg/kg every 2 weeks (group B) or no prophylaxis (group C). The annualized bleeding rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events in comparison to those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The authors concluded that emicizumab prophylaxis led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A.

The causal association of vitamin D deficiency with anemia risk still remains debatable. The role of vitamin D in risk for anemia needs to be examined in further studies.